Unlocking Neuroprotection: Simultaneous Suppression of Mitochondrial Energetic Collapse and Oxidative-Inflammatory Vortex for Ischemia-Reperfusion Brain Injury

The strategy of restoring mitochondrial function by modulating mitochondrial membrane potential (MMP) through uncoupling protein 2 (UCP2) offers significant therapeutic potential against cerebral ischemia-reperfusion injury (CIRI). However, traditional strategies ignored elevation of mitochondrial reactive oxygen species (mtROS) resulting from UCP2 inhibition, resulting in poor therapeutic effects. Here, we reported a multifunctional SGB nanomedicine formed by pioneering the prepolymerization of the UCP2 inhibitor genipin and glycine and a cerebral infarction targeting peptide via a metastable imine bond. After intravenous injection, SGB was highly targeted to affected brain tissue and reached neuronal mitochondria. SGB could not only restore MMP by cleaving the metastable imine bond to release genipin to inhibit overexpressed UCP2, but also simultaneously eliminated excessive mtROS. Compared with traditional UCP2 inhibition, SGB could not only significantly improve the bioavailability of genipin and reduce systemic side effects, but also effectively protected neuronal mitochondria, reduced endoplasmic reticulum stress and inhibited the inflammatory storm of microglia, ultimately significantly reduced neuronal apoptosis. Correspondingly, SGB nearly reversed CIRI with a low 5 mg/kg dose. This innovative approach redefines the role of UCP2 inhibition and provides a framework for the treatment of CIRI by maintaining mitochondrial function.